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Rab4A organizes endosomal domains for sorting cargo to lysosome-related organelles

Nag, S; Rani, S; Mahanty, S; Bissig, C; Arora, P; Azevedo, C; Saiardi, A; ... Setty, SR; + view all (2018) Rab4A organizes endosomal domains for sorting cargo to lysosome-related organelles. Journal of Cell Science , 131 (18) , Article jcs216226. 10.1242/jcs.216226. Green open access

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Abstract

Sorting endosomes (SEs) are the regulatory hubs for sorting cargo to multiple organelles, including lysosome-related organelles such as melanosomes in melanocytes. In parallel, melanosome biogenesis is initiated from SEs with the processing and sequential transport of melanocyte-specific proteins toward maturing melanosomes. However, the mechanism of cargo segregation on SEs is largely unknown. RNAi screening in melanocytes revealed that knockdown of Rab4A results in defective melanosome maturation. Rab4A-depletion increases vacuolar endosomes and disturbs the cargo sorting, which in turn lead to the mislocalization of melanosomal proteins to lysosomes, cell surface and exosomes. Rab4A localizes to the SEs and forms endosomal complex with AP-3 adaptor, Rabenosyn-5 effector and KIF3 motor, which possibly coordinates cargo segregation on SEs. Consistently, inactivation of Rabenosyn-5 or KIF3A/B phenocopied the defects observed in Rab4A-knockdown melanocytes. Further, Rabenosyn-5 associates with Rabaptin-5 or Rabip4/4' and differentially regulate cargo sorting from SEs. Thus, Rab4A acts a key regulator of cargo segregation on SEs.

Type: Article
Title: Rab4A organizes endosomal domains for sorting cargo to lysosome-related organelles
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1242/jcs.216226
Publisher version: https://doi.org/10.1242/jcs.216226
Language: English
Additional information: This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
Keywords: AP-3, KIF3, Melanosome biogenesis, Rab4A, RabIP4′, Rabaptin-5, Rabenosyn-5, Sorting endosome
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Lab for Molecular Cell Bio MRC-UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10056634
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